(Interferon)
Interferon (hereinafter referred to as IFN) was, at first, discovered as a virus-inhibiting substance, but thereafter was shown to be a substance that bears varied biological and immunological activities. From fairly long ago, IFN was known to be effective in inhibiting cell proliferation [Rubin, B. Y. et al. (1980): Proc. Natl. Acad. Sci. U.S.A, 77, 5928]. Further, with the recent advance of immunological science, it has come revealed that IFN can activate natural killer cells and other cells having antibody-dependent cell cytotoxicity which are supposed to take part in what is called immunological surveillance mechanism of cancer, so as to enhance the antitumor activity of those cells [Catalona, W. J. et al. (1981): Nature, 291, 77]. It has also been shown that IFN enhances the activity of cytotoxic T-cell [Lindahl, P. et al. (1972): Proc. Natl. Acad. Sci., 69, 721], and activates macrophages to change them to ones with antitumor actions [Le, J. et al. (1983): J. Immunol., 131, 2821]. These findings indicate the possibilities of IFN as an antitumor agent.
According to differences in physiological, biochemical and immunological properties of proteins, or in producing cells and inducing methods, HuIFNs are classified into three groups, which are called IFN-.alpha., IFN-.beta., and IFN-.gamma., respectively [Stewart II, W. E. et al. (1980): Nature, 286, 110].
Among others, IFN-.gamma. has an ability to inhibit cell proliferation at much lower concentrations comparing with IFN-.alpha., and IFN-.gamma. [Rubin, B. Y. et al. (1980): Proc Natl. Acad. Sci. U.S.A., 77, 5928], and also to activate cells, including natural killer cell, killer T-cell, K-cell and macrophage, which act on the basis of what is called immunological surveillance mechanism of cancer. Great expectations therefore are held by clinical application for IFN-.gamma..
HuIFN-.gamma. is found to have molecular weight of 20,000 or 25,000 [Yip, Y. K. et al. (1982) Proc. Natl. Acad. Sci. U.S.A., 79. 1820]. HuIFN-.gamma. is a glycoprotein having 143 amino acids and only one gene coding for HuIFN-.gamma. is known [Gray, P. W. et al. (1982): Nature, 295, 503].
HuIFN-.gamma. is known to be induced with human lymphocytes stimulated by phytohemaagglutinin, staphylococcal enterotoxin A, concanavalin A, or galactose oxidase [Wheelock, E. F. (1965): Science, 149, 310; Langford, M. P. et al. (1979): Infect Immun , 26, 36; de Lay, M. et al. (1980): Eur. J. Immunol., 10, 877; Dianzani, F. et al. (1979): Infect. Immun., 25, 879]. Nevertheless, since these producing methods necessitate consumption of large amounts of fresh human lymphocytes, mass-production of HuIFN-.gamma. as a therapeutic drug by such means is made difficult. Recently the realization of cloning of cDNA has made the production of HuIFN-.gamma.-like protein by Escherichia coli possible [Gray, P. W. et al (1982): Nature, 295, 503]. However, since the mechanisms of protein synthesis in animal cells are different from those of microorganisms, IFN-.gamma. produced by microorganisms are often different from those naturally produced with respect to the amino terminus of protein. Furthermore, IFN-.gamma. produced by microorganisms has no combined sugar chains, while the natural HuIFN-.gamma. has them. In such manners IFN-.gamma. produced by microbial protein synthesis system is substantially different from the natural HuIFN-.gamma., and therefore, in cases of prolonged or frequent use of such IFN-.gamma., such problems as reduction of activities of the drug by antigen-antibody reaction and allergic responses such as shock reactions remain under apprehension. According to Le et al., IFN-.gamma. produced in Escherichia coli is different from natural HuIFN-.gamma. in reactivity of antigen-antibody reaction with monoclonal antibodies, and the difference of reactivity is not due to the absence of sugar chain [Le et al. (1984): J. Immunol., 132, 1300]. While, on the other hand, it was reported that HuIFN-.gamma. was also produced by cloned T-cell line [Nathan, H. et al. (1981): Nature, 292, 842], T-cell hybridoma [Le et al. (1982): Proc. Natl. Acad. Sci. U.S.A., 79, 7857], and T-cell which was transformed by adult T-cell leukemia virus [Sugamura, K. et al. (1983): J. Immunol., 131, 1611]. These cells are believed to contain human leukemia virus as provirus, or to release virus particles out of themselves, and are therefore still problematical with respect to potential biohazards [Sugamura, K. et al. (1983): ibid.].